New approaches to enhance drug delivery across the blood-tumor barrier are being investigated. We have demonsterated that the short-acting nitric oxide (NO) donor Proli/NO selectively opens the blood-tumor barrier in rat brain tumors, but not in normal brain, to various-sized radiotracers (up to 70 kD) and to an adenoviral vector after intracarotid infusion and does so without significant systemic effects. Proli-NO has been evaluated for its ability to selectively increase the permeability of the blood-tumor barrier to molecules of a wide range of molecular weights over a wide range of doses and infusion regimens. Further studies will focus on 1) the mechanism of selective action of nitric oxide in tumor endothelial cells, the reason for its selectivity for tumor blood vessels and 2) the determination of the active compound(s) which induce the permeability changes. Our group is also studying the NO effect on other vascular physiology, such as cerebral blood flow. Furthermore, we plan to study the pathophysiology of the capillary permeability differences between tumor vasculature and normal brain vasculature as part of an effort to develop approaches that enhance microvessel permeability to increase delivery and therapeutic efficacy of drug therapy. Treatment studies using NO donors in combination with water-soluble drugs and other therapeutic agents, such as viral vectors, in rodents are planned. Our results clearly indicate that this approach might be an effective new way to opening the BBB in patients with brain tumors to enhance delivery of biologically-active macromolecules, including chemotherapuetic agents, genetic vectors etc., to malignant brain tumors for therapy. A clinical study using PET with a small group of patients with malignant brain tumors should determine whether the tumor-selective blood-brain barrier opening to tracer molecules which has been seen in the rodent model can be reproduced in humans.